Pharmacokinetics of adriamycin and tissue penetration in murine ovarian cancer.

Abstract

Abstract The penetration of Adriamycin into tumor cells and the pharmacokinetics of Adriamycin i.v. and i.p. were examined in C3HeB/FeJ mice with a transplantable ovarian cancer. Adriamycin was previously demonstrated to be effective therapy in this model only via the i.p. route. Adriamycin-specific intranuclear fluorescence was detected in ascites tumor cells within 1 min following an i.p. dose but was undetectable at any time following an equitoxic i.v. dose. Adriamycin-specific fluorescence was observed after an i.p. dose in all the tumor cells coating the diaphragm. After an i.v. dose, there was only faint and patchy intranuclear fluorescence in tumor cells coating the diaphragm. Adriamycin i.p. penetrated only into the outermost 4 to 6 cell layers of intraabdominal tumors, whereas after the i.v. route Adriamycin-specific fluorescence was observed in a patchy distribution throughout the tumor. The visual observations were confirmed by measurement of tissue Adriamycin levels. Over a 48-hr period, the concentration of Adriamycin and its fluorescent metabolites after i.p. administration exceeded by at least 1 log the i.v. drug level in ascites fluid, with the peak i.p. level (7.5 µg/ml) almost 30 times higher than the peak i.v. level (0.26 µg/ml). In the tumor cells, the peak level was 50 times higher after an i.p. dose, and at least a 1-log differential between i.v. and i.p. levels was maintained throughout the 48 hr studied. In contrast, the peak drug levels in heart, liver, and kidney were markedly higher after the i.v. route than after the i.p. route, with ratios of 3:1 for heart and kidney and 8:1 for liver. The differential in tissue concentrations rapidly decreased, so that by 24 hr there was no difference in drug concentration between the routes in any of the three organs. These observations explain the increased efficacy of i.p. over i.v. Adriamycin therapy in murine ovarian cancer and suggest further evaluation of this mode of therapy in suitable patients with ovarian cancer.